Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome.

Diabetologia. 2018 Feb 15;:

Authors: Habeb AM, Flanagan SE, Zulali MA, Abdullah MA, Pomahačová R, Boyadzhiev V, Colindres LE, Godoy GV, Vasanthi T, Al Saif R, Setoodeh A, Haghighi A, Haghighi A, Shaalan Y, International Neonatal Diabetes Consortium, Hattersley AT, Ellard S, De Franco E

Abstract
AIMS/HYPOTHESIS: Diabetes is one of the cardinal features of thiamine-responsive megaloblastic anaemia (TRMA) syndrome. Current knowledge of this rare monogenic diabetes subtype is limited. We investigated the genotype, phenotype and response to thiamine (vitamin B1) in a cohort of individuals with TRMA-related diabetes.
METHODS: We studied 32 individuals with biallelic SLC19A2 mutations identified by Sanger or next generation sequencing. Clinical details were collected through a follow-up questionnaire.
RESULTS: We identified 24 different mutations, of which nine are novel. The onset of the first TRMA symptom ranged from birth to 4 years (median 6 months [interquartile range, IQR 3-24]) and median age at diabetes onset was 10 months (IQR 5-27). At presentation, three individuals had isolated diabetes and 12 had asymptomatic hyperglycaemia. Follow-up data was available for 15 individuals treated with thiamine for a median 4.7 years (IQR 3-10). Four patients were able to stop insulin and seven achieved better glycaemic control on lower insulin doses. These 11 patients were significantly younger at diabetes diagnosis (p = 0.042), at genetic testing (p = 0.01) and when starting thiamine (p = 0.007) compared with the rest of the cohort. All patients treated with thiamine became transfusion-independent and adolescents achieved normal puberty. There were no additional benefits of thiamine doses >150 mg/day and no reported side effects up to 300 mg/day.
CONCLUSIONS/INTERPRETATION: In TRMA syndrome, diabetes can be asymptomatic and present before the appearance of other features. Prompt recognition is essential as early treatment with thiamine can result in improved glycaemic control, with some individuals becoming insulin-independent.
DATA AVAILABILITY: SLC19A2 mutation details have been deposited in the Decipher database ( https://decipher.sanger.ac.uk/ ).

PMID: 29450569 [PubMed - as supplied by publisher]

Pharmacogenomics-guided policy in opioid use disorder (OUD) management: An ethnically-diverse case-based approach.

Addict Behav Rep. 2017 Dec;6:8-14

Authors: Ettienne EB, Chapman E, Maneno M, Ofoegbu A, Wilson B, Settles-Reaves B, Clarke M, Dunston G, Rosenblatt K

Abstract
Introduction: Opioid use disorder (OUD) is characterized by a problematic pattern of opioid use leading to clinically-significant impairment or distress. Opioid agonist treatment is an integral component of OUD management, and buprenorphine is often utilized in OUD management due to strong clinical evidence for efficacy. However, interindividual genetic differences in buprenorphine metabolism may result in variable treatment response, leaving some patients undertreated and at increased risk for relapse. Clinical pharmacogenomics studies the effect that inherited genetic variations have on drug response. Our objective is to demonstrate the impact of pharmacogenetic testing on OUD management outcomes.
Methods: We analyzed a patient who reported discomfort at daily buprenorphine dose of 24 mg, which was a mandated daily maximum by the pharmacy benefits manager. Regular urine screenings were conducted to detect the presence of unauthorized substances, and pharmacogenetic testing was used to determine the appropriate dose of buprenorphine for OUD management.
Results: At the 24 mg buprenorphine daily dose, the patient had multiple relapses with unauthorized substances. Pharmacogenetic testing revealed that the patient exhibited a cytochrome P450 3A4 ultrarapid metabolizer phenotype, which necessitated a higher than recommended daily dose of buprenorphine (32 mg) for adequate OUD management. The patient exhibited a reduction in the number of relapses on the pharmacogenetic-based dose recommendation compared to standard dosing.
Conclusion: Pharmacogenomic testing as clinical decision support helped to individualize OUD management. Collaboration by key stakeholders is essential to establishing pharmacogenetic testing as standard of care in OUD management.

PMID: 29450233 [PubMed]

Therapeutic Lowering of Lipoprotein(a): A Role for Pharmacogenetics?

Circ Genom Precis Med. 2018 Feb;11(2):e002052

Authors: Boffa MB, Koschinsky ML

PMID: 29449330 [PubMed - in process]

A study on the genetic polymorphisms of CYP3A5 among the Orang Asli in Malaysia using next generation sequencing platform.

Ann Hum Biol. 2018 Feb 15;:1-12

Authors: Ang GY, Yu CY, Johari James R, Ahmad A, Abdul Rahman T, Mohd Nor F, Shaari SA, Ismail AI, Teh LK, Salleh MZ

Abstract
CYP3A5 is the predominant subfamily of biotransformation enzymes in the liver and the genetic variations in CYP3A5 are an important determinant of interindividual and interethnic differences in CYP3A-mediated drug disposition and response. This study aims to investigate the genetic polymorphisms of CYP3A5 among the Orang Asli in Peninsular Malaysia using next generation sequencing platform. Genomic DNAs were extracted from blood samples of the three main Orang Asli tribes and whole-genome sequencing was performed. A total of 61 single nucleotide polymorphisms were identified and all the SNPs were located in introns except rs15524 which is in the 3'UTR and 11 of these polymorphisms were novel. Two allelic variants and three genotypes were identified in the Orang Asli. The major allelic variant was the non-functional CYP3A5*3 (66.4%). The percentages of Orang Asli with CYP3A5*3/*3 (47.2%) and CYP3A5*1/*3 (38.1%) genotypes are more than twice the percentage of Orang Asli with CYP3A5*1/*1 (14.8%) genotype. Almost half of the Orang Asli harboured CYP3A5 non-expressor genotype (CYP3A5*3/*3). The predominance of the CYP3A5 non-expressor genotype among the Orang Asli was unraveled and the findings in this study may serve as a guide for the optimiszation of pharmacotherapy for the Orang Asli community.

PMID: 29447003 [PubMed - as supplied by publisher]

Crohn's Disease Candidate Gene Alleles Predict Time to Progression from Inflammatory B1 to Stricturing B2, or Penetrating B3 Phenotype.

Genet Test Mol Biomarkers. 2018 Feb 15;:

Authors: Pernat Drobež C, Ferkolj I, Potočnik U, Repnik K

Abstract
AIM: Crohn's disease (CD) patients are mostly diagnosed with the uncomplicated inflammatory form of disease; however, the majority of them will progress to complicated stricturing or penetrating disease over time. It is important to identify patients at risk for disease progression at an early stage. The aim of our study was to examine the role of 33 candidate CD genes as possible predictors of disease progression and their influence on time to progression from an inflammatory to a stricturing or penetrating phenotype.
METHODS: Patients with an inflammatory phenotype at diagnosis were followed for 10 years and 33 CD-associated polymorphisms were genotyped. To test for association with CD, 449 healthy individuals were analyzed as the control group.
RESULTS: Ten years after diagnosis, 39.1% of patients had not progressed beyond an inflammatory phenotype, but 60.9% had progressed to complicated disease, with average time to progression being 5.91 years. Association analyses of selected single nucleotide polymorphisms (SNPs) confirmed associations with CD for 12 SNPs. Furthermore, seven loci were associated with disease progression, out of which SNP rs4263839 in the gene TNFSF15 showed the strongest association with disease progression and the frameshift mutation rs2066847 in the gene NOD2 showed the strongest association with time to progression.
CONCLUSIONS: The results of our study identified specific genetic biomarkers as useful predictors of both disease progression and speed of disease progression in patients with CD.

PMID: 29446656 [PubMed - as supplied by publisher]

Significant Prevalence of NR3C1 Mutations in incidentally discovered Bilateral Adrenal Hyperplasia: Results of the French MUTA-GR Study.

Eur J Endocrinol. 2018 Feb 14;:

Authors: Vitellius G, Trabado S, Hoeffel-Fornes C, Bouligand J, Bennet A, Castinetti F, Decoudier B, Guiochon-Mantel A, Lombes M, Delemer B

Abstract
Recently discovered mutations of NR3C1 gene, encoding for the Glucocorticoid Receptor (GR), in patients with glucocorticoid resistance and bilateral adrenal incidentalomas prompted us to investigate whether GR mutations might be associated with adrenal hyperplasia.
OBJECTIVE: The multicenter French Clinical Research Program (Muta-GR) was set up to determine the prevalence of GR mutations and polymorphisms in patients harboring bilateral adrenal incidentalomas associated with hypertension and/or biological hypercortisolism without clinical Cushing's signs.
RESULTS: One hundred patients were included in whom NR3C1 sequencing revealed five original heterozygous GR mutations that impaired GR signaling in vitro. Mutated patients presented with mild glucocorticoid resistance defined as elevated Urinary-Free Cortisol (1.7±0.7 vs 0.9±0.8 upper limit of normal range, P=0.006), incomplete 1mg dexamethasone suppression test without suppressed 8-AM adrenocorticotrophin levels (30.9±31.2 vs 16.2±17.5 pg/mL) compared to the non-mutated patients. Potassium and aldosterone levels were lower in mutated patients (3.6±0.2 vs 4.1±0.5 mmol/L, P=0.01, and 17.3±9.9 vs 98.6±115.4 pg/mL, P=0.0011, respectively) without elevated renin levels, consistent with pseudohypermineralocorticism. Ex-vivo characterization of mutated patients' fibroblasts demonstrated GR haploinsufficiency as revealed by below-normal glucocorticoid induction of FKBP5 gene expression. There was no association between GR polymorphisms and adrenal hyperplasia in this cohort, except an over-representation of BclI polymorphism.
CONCLUSION: The 5% prevalence of heterozygous NR3C1 mutations discovered in our series is higher than initially thought and encourages GR mutation screening in patients with adrenal incidentalomas to unambiguously differentiate from Cushing's states and to optimize personalized follow-up.

PMID: 29444898 [PubMed - as supplied by publisher]

Association between circulating levels of sex steroid hormones and esophageal adenocarcinoma in the FINBAR Study.

PLoS One. 2018;13(1):e0190325

Authors: Petrick JL, Falk RT, Hyland PL, Caron P, Pfeiffer RM, Wood SN, Dawsey SM, Abnet CC, Taylor PR, Guillemette C, Murray LJ, Anderson LA, Cook MB

Abstract
BACKGROUND: Esophageal adenocarcinoma (EA) is characterized by a strong male predominance. Sex steroid hormones have been hypothesized to underlie this sex disparity, but no population-based study to date has examined this potential association.
METHODS: Using mass spectrometry and ELISA, we quantitated sex steroid hormones and sex hormone binding globulin, respectively, in plasma from males- 172 EA cases and 185 controls-within the Factors Influencing the Barrett/Adenocarcinoma Relationship (FINBAR) Study, a case-control investigation conducted in Northern Ireland and Ireland. Multivariable adjusted logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between circulating hormones and EA.
RESULTS: Higher androgen:estrogen ratio metrics were associated with increased odds of EA (e.g., testosterone:estradiol ratio ORQ4 v. Q1 = 2.58, 95%CI = 1.23-5.43; Ptrend = 0.009). All estrogens and androgens were associated with significant decreased odds of EA. When restricted to individuals with minimal to no decrease in body mass index, the size of association for the androgen:estrogen ratio was not greatly altered.
CONCLUSIONS: This first study of sex steroid hormones and EA provides tentative evidence that androgen:estrogen balance may be a factor related to EA. Replication of these findings in prospective studies is needed to enhance confidence in the causality of this effect.

PMID: 29342161 [PubMed - indexed for MEDLINE]

High lncRNA H19 expression as prognostic indicator: data mining in female cancers and polling analysis in non-female cancers.

Oncotarget. 2017 Jan 03;8(1):1655-1667

Authors: Peng L, Yuan XQ, Liu ZY, Li WL, Zhang CY, Zhang YQ, Pan X, Chen J, Li YH, Li GC

Abstract
Upregulation of lncRNA H19 expression is associated with an unfavorable prognosis in some cancers. However, the prognostic value of H19 in female-specific cancers has remained uncharacterized. In this study, the prognostic power of high H19 expression in female cancer patients from the TCGA datasets was analyzed using Kaplan-Meier survival curves and Cox's proportional hazard modeling. In addition, in a meta-analysis of non-female cancer patients from TCGA datasets and 12 independent studies, hazard ratios (HRs) with 95% confidence interval (CI) for overall survival (OS) and disease-free survival (DFS)/relapse-free survival (RFS)/metastasis-free survival (MFS)/progression-free survival (PFS) were pooled to assess the prognostic value of high H19 expression. Kaplan-Meier analysis revealed that patients with uterine corpus cancer and higher H19 expression had a shorter OS (HR=2.710, p<0.05), while females with cervical cancer and increased H19 expression had a shorter RFS (HR=2.261, p<0.05). Multivariate Cox regression analysis showed that high H19 expression could independently predict a poorer prognosis in cervical cancer patients (HR=4.099, p<0.05). In the meta-analysis, patients with high H19 expression showed a poorer outcome in non-female cancer (p<0.05). These results suggest that high lncRNA H19 expression is predictive of an unfavorable prognosis in two female cancers (uterine corpus endometrioid cancer and cervical cancer) as well as in non-female cancer patients.

PMID: 27926484 [PubMed - indexed for MEDLINE]

A novel form of capsaicin-modified amygdala LTD mediated by TRPM1.

Neurobiol Learn Mem. 2016 Dec;136:1-12

Authors: Gebhardt C, von Bohlen Und Halbach O, Hadler MD, Harteneck C, Albrecht D

Abstract
Recently we have shown that capsaicin attenuates the strength of LTP in the lateral amygdala (LA) and demonstrated that this effect is mediated by the transient receptor potential (TRP) channel TRPV1. Here we further show that capsaicin, which is thought to act primarily through TRPV1, modifies long term depression (LTD) in the LA. Yet the application of various TRPV1 antagonists does not reverse this effect and it remains in TRPV1-deficient mice. In addition, voltage gated calcium channels, nitric oxide and CB1 receptors are not involved. Using pharmacology and TRPM1-/- mice, our electrophysiological data indicate that capsaicin-induced activation of TRPM1 channels contribute to the induction of LA-LTD. Whereas LA-LTD in general depends on the acitvation of NMDA receptors- and group II metabotropic glutamate receptors (mGluR), the modifying effect of capsaicin on LA-LTD via TRPM1 appears to be specifically mediated by group I mGluRs and in interaction with another member of the TRP family, TRPC5. Additionally, intact GABAergic transmission is required for the capsaicin-effect to take place. This is the first documentation that beside their function in the retina TRPM1 proteins are expressed in the brain and have a functional relevance in modifying synaptic plasticity.

PMID: 27633915 [PubMed - indexed for MEDLINE]

BART miRNAs: an unimaginable force in the development of nasopharyngeal carcinoma.

Eur J Cancer Prev. 2017 Mar;26(2):144-150

Authors: Wang Y, Guo Z, Shu Y, Zhou H, Wang H, Zhang W

Abstract
Nasopharyngeal carcinoma (NPC) is a head and neck cancer that represents a major health burden in Southern China and Southeast Asia. Although the close association of NPC with Epstein-Barr virus (EBV) infection has been demonstrated, its exact role in the pathogenesis of this malignancy is still unclear. The expression of EBV-encoded microRNAs, especially BART miRNAs, which are encoded from the BamHI-A region of the viral genome, is detected at a high level in NPC. miRNAs are small noncoding mRNAs that can positively regulate the virus to ensure accurate expression of viral genomes and to modify the gene expression of host cells by negative regulation. Accumulating evidence suggests that ebv-mir-BARTs play a critical role in host cell survival, immune escape, cell proliferation, cell apoptosis, and cancer metabolism, promoting the generation of NPC. This review will summarize our current understanding of the nature and function of ebv-mir-BARTs in NPC.

PMID: 26909566 [PubMed - indexed for MEDLINE]

Implementing pharmacogenomics decision support across seven European countries: The Ubiquitous Pharmacogenomics (U-PGx) project.

J Am Med Inform Assoc. 2018 Feb 09;:

Authors: Blagec K, Koopmann R, Crommentuijn-van Rhenen M, Holsappel I, van der Wouden CH, Konta L, Xu H, Steinberger D, Just E, Swen JJ, Guchelaar HJ, Samwald M

Abstract
Clinical pharmacogenomics (PGx) has the potential to make pharmacotherapy safer and more effective by utilizing genetic patient data for drug dosing and selection. However, widespread adoption of PGx depends on its successful integration into routine clinical care through clinical decision support tools, which is often hampered by insufficient or fragmented infrastructures. This paper describes the setup and implementation of a unique multimodal, multilingual clinical decision support intervention consisting of digital, paper-, and mobile-based tools that are deployed across implementation sites in seven European countries participating in the Ubiquitous PGx (U-PGx) project.

PMID: 29444243 [PubMed - as supplied by publisher]

Polymorphisms of drug-metabolizing enzyme CYP2E1 in Chinese Uygur population.

Medicine (Baltimore). 2018 Feb;97(7):e9970

Authors: Zhu L, He Y, Niu F, Yan M, Li J, Yuan D, Jin T

Abstract
Pharmacogenetics is the genetic basis of pharmacokinetics, genetic testing, and clinical management in diseases. Evaluation about genetic alterations of drug metabolizing enzymes in human genome contributes toward understanding the interindividual and interethnic variability for clinical response to potential toxicants. CYP2E1 gene encodes a drug-metabolizing enzyme that metabolizes mostly small, polar molecules, including toxic laboratory chemicals. The aim of this study was to investigate CYP2E1 polymorphisms and gene profile in a Chinese Uygur population. Frequencies for the CYP2E1 mutated alleles and genotypes were screened in 100 unrelated random healthy Uygur volunteers. PCR and direct sequencing revealed a total of 32 polymorphisms, of which 5 novel mutations were presented. Rs 943975 was the most common single nucleotide polymorphism (SNP). The allele frequencies of CYP2E11A, 4, 7A, and 7C were 65.5, 2, 19.5, and 13%, respectively. The most common genotype combinations were CYP2C191A/1A (43%) and 1A/7C (24%). Functional prediction for 2 nonsynonymous mutations G173S and V179I was performed using MutationTaster, sorting intolerant from tolerant, and PolyPhen-2. The observations of the present study give rise to useful information on CYP2E1 polymorphisms in Chinese Uygur individuals. The results suggest important clinical implications for the use of medications metabolized by CYP2E1 among Uygurs.

PMID: 29443789 [PubMed - in process]

Improving decision making on DPYD and UGT1A1*28 patients' profiling with an innovative reimbursement strategy.

Pharmacogenomics. 2018 Feb 14;:

Authors: Roncato R, Cecchin E, Toffoli G

PMID: 29441806 [PubMed - as supplied by publisher]

Genetic polymorphisms of HTR2C, LEP and LEPR on metabolic syndromes in patients treated with atypical antipsychotic drugs.

J Pharm Pharmacol. 2018 Feb 13;:

Authors: Puangpetch A, Unaharassamee W, Jiratjintana N, Koomdee N, Sukasem C

Abstract
OBJECTIVE: Single nucleotide polymorphisms in serotonin 2C receptor (HTR2C), leptin (LEP), and leptin receptor (LEPR) genes are reportedly associated with the presence of metabolic syndrome (MS). We investigated whether HTR2C:rs518147 (-697G/C), rs12836771 (A/G), LEP: rs7799039 (-2548G/A) and LEPR:rs1137101 (668A/G) are related to MS in psychotic disorder patients treated with atypical antipsychotics.
METHODS: A cross-sectional study including 200 patients was conducted; genetic polymorphisms in HTR2C (rs518147 and rs12836771), LEP (rs7799039) and LEPR (rs1137101) were genotyped. The presence of MS was evaluated according to the 2005 International Diabetes Federation (IDF) Asia criteria. The associations of genetic factors with the presence of MS are analysed.
KEY FINDINGS: Two SNPs in the HTR2C gene but not LEP and LEPR were associated with the presence of MS after adjustment for the combination of atypical antipsychotics. With respect to the effect of gender after treatment with risperidone and clozapine was statistically significant. Moreover, genotype combinations had no effect on MS.
CONCLUSIONS: Therefore, HTR2C genetic variants may be involved in the susceptibility to MS in patients treated with atypical antipsychotics. Additionally, there was a gender effect in the presence of MS. No effect of LEP or LEPR polymorphisms or the combination of HTR2C-LEP and HTR2C-LEPR was observed for the presence of MS.

PMID: 29441581 [PubMed - as supplied by publisher]

Evaluation of alteration in hepatic and intestinal BCRP function in vivo due to ABCG2 c.421C>A polymorphism based on PBPK analysis of rosuvastatin.

Drug Metab Dispos. 2018 Feb 12;:

Authors: Futatsugi A, Toshimoto K, Yoshikado T, Sugiyama Y, Kato Y

Abstract
Polymorphism c.421C>A in ABCG2 gene is thought to reduce the activity of breast cancer resistance protein (BCRP), a xenobiotic transporter, although it is not clear which organ(s) contributes to the polymorphism-associated pharmacokinetic change. The aim of the present study was to quantitatively estimate the influence of c.421C>A on intestinal and hepatic BCRP activity, using a physiologically based pharmacokinetic (PBPK) model of rosuvastatin developed from clinical data and several in vitro studies. Simultaneous fitting of clinical data for orally and intravenously administered rosuvastatin, obtained in human subjects without genotype information was first performed with the PBPK model to estimate intrinsic clearance for hepatic elementary process. The fraction of BCRP activity in 421CA and 421AA (fca and faa values, respectively) with respect to that in 421CC subjects was then estimated based on extended clearance concepts and simultaneous fitting to oral administration data for the three genotypes (421CC, 421CA, and 421AA). On the assumption that c.421C>A affects both intestinal and hepatic BCRP, clinical data in each genotype were well reproduced by the model, and the estimated terminal half-life was compatible with the observed values. The assumption that c.421C>A only affects either intestinal or hepatic BCRP gave poorer agreement with observed values. The faa values obtained on the former assumption were 0.48-0.54. Thus, PBPK model analysis enabled quantitative evaluation of alteration in BCRP activity due to c.421C>A, and BCRP activity in 421AA was estimated as half that in 421CC.

PMID: 29440178 [PubMed - as supplied by publisher]

A review of ustekinumab in the treatment of psoriatic arthritis.

Immunotherapy. 2018 Feb 14;:

Authors: Roberts J, O'Rielly DD, Rahman P

Abstract
Psoriatic arthritis is an inflammatory arthritis associated with psoriasis. The IL-23/IL-17 axis is an important pathway in the development of psoriatic disease. Ustekinumab is a fully human monoclonal IgG1 antibody that binds to the p40 subunit of IL-12 and IL-23, which, in turn, inhibits downstream signaling pathways. PSUMMIT-1 and PSUMMIT-2 are two pivotal Phase III trials demonstrating global improvement in primary and secondary outcomes including inhibition of radiographic progression. Therapeutic benefit of ustekinumab for synovitis appears independent of previous disease modifying antirheumatic disease or anti-TNF exposure. At present, the data support the use of ustekinumab in the treatment of psoriatic arthritis after the failure of NSAIDs and conventional disease modifying antirheumatic diseases as an alternative to, or after failure of an anti-TNF agent.

PMID: 29439608 [PubMed - as supplied by publisher]

NAT2 slow acetylator associated with anti-tuberculosis drug-induced liver injury in Thai patients.

Int J Tuberc Lung Dis. 2016 Oct;20(10):1364-1369

Authors: Wattanapokayakit S, Mushiroda T, Yanai H, Wichukchinda N, Chuchottawon C, Nedsuwan S, Rojanawiwat A, Denjanta S, Kantima T, Wongyai J, Suwankesawong W, Rungapiromnan W, Kidkeukarun R, Bamrungram W, Chaiwong A, Suvichapanich S, Mahasirimongkol S, Tokunaga K

Abstract
BACKGROUND: Anti-tuberculosis drug-induced liver injury (AT-DILI) is one of the most common forms of drug-induced liver injury (DILI) in high tuberculosis (TB) burden countries. Among anti-tuberculosis drugs, isoniazid is the main cause of hepatotoxicity in patients with AT-DILI.
OBJECTIVE: To investigate the association of AT-DILI with N-acetyltransferase 2 (NAT2) genotype status in Thai TB patients.
METHODS: We enrolled 53 patients diagnosed with AT-DILI and 85 patients who tolerated anti-tuberculosis treatment as controls. Acetylator status was determined based on the inferred NAT2 haplotypes from four common single-nucleotide polymorphisms (SNPs) in Thais using Sanger sequencing.
RESULTS: Phenotype frequencies of the NAT2 acetylator in AT-DILI patients were respectively 71.7%, 22.6% and 5.7% for slow, intermediate and rapid acetylators. Among slow, intermediate, and rapid acetylators in treatment tolerant controls, phenotype frequencies were respectively 22.4%, 62.4% and 15.3%. Slow NAT2 acetylators demonstrated a significant association with risk of AT-DILI. The odds ratio of comparing slow NAT2 acetylator in DILI patients and tolerance was 8.80 (95%CI 4.01-19.31, P = 1.53 × 10-8).
CONCLUSIONS: Slow acetylator status in the NAT2 genotype is a significant risk factor for DILI in Thai patients with TB. This evidence provides confirmatory data in support of the role of NAT2 in AT-DILI in the Thai population.

PMID: 27725049 [PubMed - indexed for MEDLINE]

Posttranscriptional regulation of UGT2B10 hepatic expression and activity by alternative splicing.

Drug Metab Dispos. 2018 Feb 09;:

Authors: Labriet A, Allain EP, Rouleau M, Audet-Delage Y, Villeneuve L, Guillemette C

Abstract
The detoxification enzyme UDP-glucuronosyltransferase UGT2B10 is specialized in the N-linked glucuronidation of many drugs and xenobiotics. Preferred substrates possess tertiary aliphatic amines and heterocyclic amines such as tobacco carcinogens and several anti-depressants and anti-psychotics. We hypothesized that alternative splicing (AS) constitutes a mean to regulate steady state levels of UGT2B10 and enzyme activity. We established the transcriptome of UGT2B10 in normal and tumoral tissues of multiple individuals. Highest expression was in the liver, where ten AS transcripts represented 50% of the UGT2B10 transcriptome in 50 normal livers and 44 hepatocellular carcinomas. One abundant class of transcripts involves a novel exonic sequence and leads to two alternative (alt.) variants with novel in-frame C-termini of 10 or 65 amino acids. Their hepatic expression was highly variable among individuals, correlated with canonical transcript levels, and was 3.5 fold higher in tumors. Evidence for their translation in liver tissues was acquired by mass spectrometry. In cell models, they co-localized with the enzyme and influenced the conjugation of amitriptyline and levomedetomidine by repressing or activating the enzyme (40-70%; P<0.01), in a cell context-specific manner. A high turnover rate for the alt. proteins, regulated by the proteasome, was observed in contrast to the more stable UGT2B10 enzyme. Moreover, a drug-induced remodelling of UGT2B10 splicing was demonstrated in the HepaRG hepatic cell model, which favored alt. variants expression over the canonical transcript. Our findings support a significant contribution of AS in the regulation of UGT2B10 expression in the liver with an impact on enzyme activity.

PMID: 29438977 [PubMed - as supplied by publisher]

Penetration of cefotaxime into cerebrospinal fluid in neonates and young infants.

Antimicrob Agents Chemother. 2018 Feb 05;:

Authors: Chen XK, Shi HY, Leroux S, Xu HY, Zhou Y, Zheng Y, Huang X, Li Y, Jacqz-Aigrain E, Zhao W

Abstract
Objective: Cefotaxime is the first-line treatment for meningitis in neonates and young infants. However, limited data on cefotaxime cerebrospinal fluid (CSF) concentrations in neonates and young infants were available. The aim of the present study is to evaluate the penetration of cefotaxime into CSF in neonates and young infants.Methods: Blood and CSF samples were collected from neonates and young infants treated with cefotaxime using an opportunistic pharmacokinetic sampling strategy and concentrations were quantified by HPLC-MS/MS. The analysis was performed using NONMEM and R software.Results: Thirty neonates and young infants (PMA range: 25.4-47.4 weeks) were included. A total of 67 plasma and 30 CSF samples were available for analysis. Cefotaxime plasma and CSF concentrations ranged from 2.30 to 175.42 mg/liter, and from 0.39 to 25.38 mg/liter, respectively. The median ratio of CSF to plasma concentrations was 0.28 (range 0.06-0.76). Monte Carlo simulation demonstrated that 88.4% and 63.9% of hypothetical neonates treated with 50 mg/kg TID would reach the pharmacodynamic target (70% fT>MIC) using the standard EUCAST MIC susceptibility breakpoint of 2 mg/liter and 4 mg/liter, respectively.Conclusion: The penatration of cefotaxime into CSF was evaluted in neonates and young infants using an opportunistic sampling appoarch. A dosage regimen of 50 mg/kg TID could cover the most causative pathogens with MIC<2 mg/liter. The individual dosage adaptation was required for more resistant bacterial strains such as Staphylococcus aureus.

PMID: 29437625 [PubMed - as supplied by publisher]

Evaluation of prescriber responses to pharmacogenomics clinical decision support for thiopurine S-methyltransferase testing.

Am J Health Syst Pharm. 2018 Feb 15;75(4):191-198

Authors: Ubanyionwu S, Formea CM, Anderson B, Wix K, Dierkhising R, Caraballo PJ

Abstract
PURPOSE: Results of a study of prescribers' responses to a pharmacogenomics-based clinical decision support (CDS) alert designed to prompt thiopurine S-methyltransferase (TPMT) status testing are reported.
METHODS: A single-center, retrospective, chart review-based study was conducted to evaluate prescriber compliance with a pretest CDS alert that warned of potential thiopurine drug toxicity resulting from deficient TPMT activity due to TPMT gene polymorphism. The CDS alert was triggered when prescribers ordered thiopurine drugs for patients whose records did not indicate TPMT status or when historical thiopurine use was documented in the electronic health record. The alert pop-up also provided a link to online educational resources to guide thiopurine dosing calculations.
RESULTS: During the 9-month study period, 500 CDS alerts were generated: in 101 cases (20%), TPMT phenotyping or TPMT genotyping was ordered; in 399 cases (80%), testing was not ordered. Multivariable regression analysis indicated that documentation of historical thiopurine use was the only independent predictor of test ordering. Among the 99 patients tested subsequent to CDS alerts, 70 (71%) had normal TPMT activity, 29 (29%) had intermediate activity, and none had deficient activity. The online resources provided thiopurine dosing recommendations applicable to 24 patients, but only 3 were prescribed guideline-supported doses after CDS alerts.
CONCLUSION: The pretest CDS rule resulted in a large proportion of neglected alerts due to poor alerting accuracy and consequent alert fatigue. Prescriber usage of online thiopurine dosing resources was low.

PMID: 29436466 [PubMed - in process]